In the near future, a Japanese scientist engineers a powered exoskeleton called "Infinite Stratos" (IS). Possessing technology and combat capabilities far more advanced than any other weapon system, the IS threatens to destabilize the world. Faced with such an overpowering weapon, the nations of the world enact the "Alaska Treaty", which states that IS will never be used for military combat and that existing IS technology must be equally distributed to all nations, to prevent any one nation for dominating the others. The introduction of the IS does however have a major effect on society. As IS can only be operated by women, the power balance between men and women is broken, with women coming to dominate society over men.

Ten years after the first IS were introduced, the world has entered a new age of peace. The peace is shattered, however, by an unexpected discovery. A 15 year old Japanese boy, named Ichika Orimura, is discovered to be capable of operating an IS. Realizing the potential, Ichika is forced by the Japanese government to attend the prestigious Infinite Stratos Academy, an international academy where IS pilots from all over the world are trained. Thus his busy school life surrounded by girls begins.